Diklofenak-Darnitsa

General characteristics. Structure:

Active ingredient: diclofenac;

1 ml of solution contains diclofenac of sodium 25 mg;

excipients: a mannitol (Е 421), sodium metabisulphite (Е 223), benzyl alcohol, propylene glycol, sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics. Diklofenak-Darnitsa contains sodium diclofenac, nonsteroid connection with the expressed antirheumatic, antiinflammatory, anesthetizing and febrifugal properties. Oppression of biosynthesis of prostaglandins which was shown in experiments is considered the main mechanism of its action. Prostaglandins play an important role in emergence of an inflammation, pain and fever.

At rheumatic diseases the antiinflammatory and anesthetizing properties of drug cause the clinical answer which is characterized by the expressed disappearance of signs and symptoms: rest pains and at the movement, morning rigidity and hypostasis of joints, also noticeable improvement of motive function.

Diclofenac is capable to strengthen the expressed anesthetizing influence on moderate and heavy pains of not rheumatic origin within 15-30 minutes.

Diclofenac showed also significant effect on migraine attacks.
At posttraumatic and postoperative states with existence of an inflammation diclofenac quickly relieves spontaneous pains and pains during the movement and reduces the hypostases caused by an inflammation and wounds.

If drug is used along with opioid anesthetics for removal of postoperative pain, diclofenac significantly reduces their need.
Diklofenak-Darnitsa, solution in ampoules is especially necessary for injections to start treatment of inflammatory and degenerative rheumatic diseases and a painful state owing to an inflammation of not rheumatic origin.

Pharmacokinetics. Absorption.
After introduction of 75 mg of diclofenac by an injection absorption begins immediately, and average maximum concentration in plasma, components about 2,5 micrograms/ml (8 µmol/l), are reached approximately after 20 min. The volume of absorption can linearly depend on dose size.
In case 75 mg of diclofenac enter by infusion within 2 hours, average maximum concentration in plasma make about 1,9 micrograms/ml (5,9 µmol/l). Shorter time of infusion leads to the highest maximum concentration in plasma while long infusions result in the concentration proportional to infusion indicators after 3-4 hours. After an intramuscular injection or reception of gastroresistant tablets or use of suppositories of concentration in a blood plasma quickly decrease right after achievement of peak levels.

The area under a curve of concentration (AUC) after intramuscular or intravenous administration is approximately twice more, than after peroral or rectal administration as about a half of active substance is metabolized during the first passing through a liver (effect of "the first passing") if the drug is administered in the peroral or rectal way.
Pharmacokinetic properties do not change after repeated introduction. In the conditions of observance of the recommended intervals of dosing of accumulation of drug does not occur.
Distribution. 99,7% of diclofenac contact serum proteins, mainly albumine (99,4%). The presumable volume of distribution makes 0,12-0,17 l/kg.
Diclofenac gets to synovial fluid where the maximum concentration are established in 2-4 hours after achievement of peak value in a blood plasma. The presumable elimination half-life made from 3 to 6 hours of synovial fluid. In 2 hours after achievement of level of peak value in a blood plasma of concentration of diclofenac in synovial fluid exceed this indicator in a blood plasma and remain high for 12 hours.

Biotransformation.
Biotransformation of diclofenac occurs partially by a glyukuronidation of an intact molecule, but mainly by a single and repeated hydroxylation and a metoksilirovaniye that leads to formation of several phenolic metabolites, the majority of which turns into a glucuronide conjugate. Two of these phenolic metabolites biologically active, however their action is expressed much less, than in diclofenac.
Removal.
The general system clearance of diclofenac in plasma makes 263 ± 56 ml/min. (average value ± SD). The terminal elimination half-life in plasma makes 1-2 hours. Four of metabolites, including two active, also have short plasma elimination half-life  1-3 hours. One metabolite, 3, has much longer plasma elimination half-life of blood. However this metabolite actually inactive.
About 60% of the entered dose are removed with urine in the form of a glyukuronidny conjugate of an intact molecule and in the form of metabolites, the majority of which also turns into glyukuronidny conjugates. Less than 1% are removed in the form of not changed substance. The remains of a dose eliminirutsya in the form of metabolites through bile with excrements.

Special groups of patients.

No difference on age dependence in absorption, metabolism or excretion of drug was observed. However at some patients of advanced age 15-minute intravenous infusion resulted in concentration in a blood plasma which was 50% higher, than it was observed at young healthy faces.

At patients with a renal failure at observance of the mode of usual dosing it is possible not to expect accumulation of active agent. At clearance of creatinine less than 10 ml/min. hydroxy metabolites levels in a blood plasma at achievement of steady state are about 4 times higher, than at normal persons.

Thus, metabolites are finally removed through bile.

At patients with chronic hepatitis or nedekompensirovannny cirrhosis the kinetics and metabolism of diclofenac are identical, as well as at patients without liver disease.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent, colourless or with slightly yellowish shade liquid with a light specific smell.

Incompatibility.

Diklofenak-Darnitsa, solution for injections cannot be mixed with other solutions for injections in one capacity.

Solutions for infusion of sodium of chloride of 0,9% or glucose of 5% without sodium bicarbonate as additive, have risk of oversaturation that can lead to formation of crystals or a deposit.

Other solutions for infusion does not follow apply.

Indications to use:

Drug at intramuscular introduction is intended for treatment:

– inflammatory and degenerative forms of rheumatism, pseudorheumatism, ankylosing spondylitis, osteoarthritis, spondylarthritis, vertebralny pain syndrome, extraarticular rheumatism;

– bad attacks of gout;

– renal and bilious gripes;

– pain and hypostasis after injuries and operations;

– heavy attacks of migraine.

Drug at introduction in the form of intravenous infusions is intended for treatment or prevention of postoperative pain.

Route of administration and doses:

The general recommendation – the dose should be selected individually, since a minimal effective dose, and it is necessary to accept during the smallest possible term.
The drug Diklofenak-Darnitsa, solution for injections not to apply more than 2 days; if necessary treatment can be continued by the tablets Diklofenak-Darnitsa.

Intramuscular injections.

For the purpose of the prevention of damage of nervous or other tissues to the place of an injection it is necessary to carry out the following rules.

The dose usually makes 1 ampoule of 75 mg a day by a deep injection to the upper outside sector of a big gluteus. In hard cases (for example, gripes), it is possible to increase a daily dose to 2 injections on 75 mg between which observe an interval in several hours (on 1 injection in each buttock). As an alternative 1 ampoule on 75 mg can be combined with other dosage forms of the drug Diklofenak-Darnitsa (for example, tablets) to the general of the maximum daily dose of 150 mg.

In the conditions of a migraine attack clinical experience is limited by cases with initial use of 1 ampoule of 75 mg, a dose enter at an opportunity at once after use diclofenac of the containing suppositories on 100 mg on the same day (if necessary). The general daily dose should not exceed 175 mg in the first day.

Intravenous infusions.

Diklofenak-Darnitsa, solution for injections, it is not necessary to enter in the form of an intravenous bolyusny injection.
Just before the beginning of infusion of Diklofenak-Darnitsa, depending on duration demanded it, it is necessary to dissolve in 100-500 ml 0,9% of solution of sodium of chloride or 5% of solution of glucose buffered by sodium bicarbonate solution for an injection (0,5 ml 8, 4% of solution or 1 ml of 4,2% or the corresponding volume of other concentration) that was taken from just open container; to add contents of 1 ampoule of the drug Diklofenak-Darnitsa to this solution. It is possible to use only transparent solutions. If in solution crystals or a deposit appear, it cannot be applied to infusion.

Two alternative modes of a drug dosing Diklofenak-Darnitsa of solution for injections are recommended. For treatment of moderate and heavy postoperative pain of 75 mg it is necessary to enter continuously of 30 minutes till 2 o'clock. If necessary treatment can be repeated in several hours, but the dose should not exceed 150 mg during any period in 24 hours.

For prevention of postoperative pain through 15 minutes – 1 hour after surgical intervention it is necessary to enter a load dose of 25-50 mg, after that it is necessary to apply continuous infusion about 5 mg/hour to the maximum daily dose of 150 mg.

Features of use:

Use during pregnancy or feeding by a breast.

Pregnancy. Diklofenak-Darnitsa it is not necessary to apply during the I-II trimesters. As well as with other non-steroidal anti-inflammatory drugs, use during  the III trimester is contraindicated owing to possible development of lack of reduction of a uterus and/or premature closing of ductus arteriosus.

Feeding period breast. As well as other non-steroidal anti-inflammatory drugs, diclofenac gets into breast milk in a small amount. Thus, in order to avoid undesirable influence on the baby Diklofenak-Darnitsa it is not necessary to apply during feeding by a breast.

Fertility. As well as other NPVS, Diklofenak-Darnitsa can affect fertility of the woman. Drug is not recommended to women who plan to become pregnant. The women having complications with fertilization or those who underwent inspection as a result of an infertilnost have to stop drug Diklofenak-Darnitsa use.

Children.

Owing to considerable influence the drug Diklofenak-Darnitsa in the form of solution for injections is not used to children.

At use of all non-steroidal anti-inflammatory drugs (NPVS) gastrointestinal bleeding, an ulcer or perforation can be lethal and can arise in any span throughout treatment, with or without preliminary symptoms or the serious gastrointestinal phenomena in the anamnesis. At patients of advanced age these phenomena have usually more serious effects. In case of developing of gastrointestinal bleeding at the patients receiving Diklofenak-Darnitsa, this medicine needs to be cancelled.

Very seldom in connection with use of NPVS, including diclofenac, serious reactions from skin were observed, including exfoliative dermatitis, Stephens-Johnson's syndrome and a toxic epidermal necrolysis. The highest risk of emergence of these reactions at patients exists at the beginning of a course of treatment, in most cases emergence of these reactions happens within the first month of treatment. Use of the drug Diklofenak-Darnitsa should be stopped at the first emergence of rash on skin, damages of mucous membranes or any other signs of hypersensitivity.

As well as at use of other NPVS, it is rare without preliminary exposure of diclofenac, there can also be allergic reactions, including anaphylactic/anaphylactoid. Sodium metabisulphite in solution for injections can lead to separate heavy reactions of hypersensitivity and a bronchospasm.

NPVS can increase risk of emergence of the serious cardiovascular trombotichesky phenomena, a myocardial infarction and stroke which can be lethal in this connection, Diklofenak-Darnitsa is not recommended to be applied to treatment of postoperative pain during operation on aortocoronary shunting.

As well as other NPVS, Diklofenak-Darnitsa thanks to the pharmakodinamichesky action can mask signs and symptoms of an infection.

Cautions.
The general. It is necessary to avoid use of the drug Diklofenak-Darnitsa with system NPVS, including the selection inhibitors of cyclooxygenase-2 in view of lack of any synergy advantage and a possibility of development of additional side effects.

It is necessary to be careful at purpose of drug to elderly people. In particular, for people of advanced age with poor health, and with low body weight it is recommended to apply the smallest effective doses to patients.

Asthma in the anamnesis. At patients with bronchial asthma, seasonal allergic rhinitis, a rhinedema (i.e. nasal polyps), chronic obstructive diseases of lungs or persistent infections of the airways (which are especially tied with allergic, similar to rhinitises, symptoms) is more often than others there are reactions to NPVS similar to an exacerbation of asthma (which are also connected with portability of analgetics / анальгетиковой asthma), a Quincke's edema or a small tortoiseshell. In this regard special precautionary measures (readiness for rendering acute management) are recommended to such patients. It also concerns patients with an allergy to other substances, for example, with skin reactions, an itch or small tortoiseshell.

Special cautions are recommended in case Diklofenak-Darnitsa is applied parenterally to patients with bronchial asthma as symptoms can become aggravated.
Influence on a digestive tract. As well as at use of other NPVS, at purpose of the drug Diklofenak-Darnitsa or with the anamnesis providing existence of stomach ulcer or intestines, bleeding or perforation medical observation and extra care is obligatory for patients with the symptoms testimonial of disturbances from the digestive tract (DT). The risk of developing of bleeding in a GIT increases with increase in a dose and at patients with an ulcer in the anamnesis, especially with complications in the form of bleeding or perforation, and at people of advanced age.

To reduce risk of toxic influence on a GIT at patients with an ulcer in the anamnesis, especially with complications in the form of bleeding or perforation, and at people of advanced age treatment is begun and supported by the smallest effective doses.

For such patients, and also patients needing the accompanying use of the medicines containing low doses of acetylsalicylic acid (ASK) or other medicines which, presumably, increase risk of undesirable impact on a GIT it is necessary to consider a question of use of a combination therapy using protective equipment (for example, inhibitors of the proton pump or a mizoprostol).
Patients with gastrointestinal toxicity in the anamnesis, especially advanced age, have to report about any unusual abdominal symptoms (especially bleedings in a GIT).

Precaution is also necessary for patients who receive the accompanying drugs which can increase risk of an ulcer or bleeding, such as system corticosteroids, anticoagulants, antitrombotichesky means or selective serotonin reuptake inhibitors.
Diklofenak-Darnitsa it is necessary to appoint with care the patient in whose anamnesis there are inflammatory diseases of intestines, such as disease Krone or nonspecific ulcer colitis and to establish careful medical observation and the appropriate measures of precaution because their state can become aggravated.
Influence on a liver. Careful medical observation is required in case Diklofenak-Darnitsa appoint to patients with the broken function of a liver as their state can become aggravated.

As well as at use of other NPVS, the level of one and more hepatic enzymes can increase. During long-term treatment (tablets or suppositories), regular observation of function of a liver as a precautionary measure is appointed the drug Diklofenak-Darnitsa. If abnormal liver functions remain or worsen if clinical signs or symptoms can be connected with the progressing liver diseases or if other manifestations are observed (for example, an eosinophilia, rash), use of the drug Diklofenak-Darnitsa should be stopped. The course of diseases, such as hepatitises, can pass without prodromal symptoms.

Cautions are necessary in case Diklofenak-Darnitsa apply to patients with a hepatic porphyria because of probability of provocation of an attack.

Influence on kidneys. As at treatment of NPVS it was reported about a delay of liquid and hypostasis, special attention should be paid to patients with dysfunction of heart or kidneys (including a functional renal failure against the background of a hypovolemia, a nephrotic syndrome, a lupoid nephropathy and dekompensirovanny cirrhosis), arterial hypertension in the anamnesis, to the patients of advanced age, patients receiving the accompanying therapy by diuretics or drugs which significantly influence renal function, and for patients with essential decrease in extracellular volume of liquid because of any reason, for example, to or after serious surgical intervention. In such cases as a precautionary measure monitoring of function of kidneys is recommended. The therapy termination usually promotes return of a state which preceded treatment.

Influence on hematologic indicators. At prolonged use of drug, as well as other NPVS, blood test monitoring is recommended. As well as other NPVS, Diklofenak-Darnitsa can temporarily oppress aggregation of thrombocytes. It is necessary to watch carefully patients with disturbances of a hemostasis.

Ability to influence speed of response at control of motor transport or work     with other mechanisms.

Patients at whom during treatment the drug Diklofenak-Darnitsa observes vision disorders, dizziness, вертиго, drowsiness or other disturbances from the central nervous system have to abstain from control of motor transport and work with other mechanisms.

Side effects:

Side reactions on drug are described in such order on frequency: very often (≥ 1/10); often (≥ 1/100, <1/10); infrequently (≥ 1/1 000, <1/100); seldom (≥ 1/10 000, <1/1 000); extremely seldom (<1/10 000), including separate messages.

The following undesirable effects include the phenomena connected with administration of the drug Diklofenak-Darnitsa of solution for injections and/or other dosage forms of diclofenac at short-term and prolonged use.

Infections and invasions: very seldom – abscess in the place of an injection.

From system of a hemopoiesis: very seldom – thrombocytopenia, a leukopenia, anemia (including hemolitic and aplastic anemias), an agranulocytosis.

From immune system: seldom – hypersensitivity, anaphylactic and pseudoanaphylactic reactions (including hypotension and shock), it is very rare – a Quincke's disease (including a face edema).

Mental disorders: very seldom – a disorientation, a depression, sleeplessness, nightmares, irritability, mental disorders.

From a nervous system: often – a headache, dizziness; seldom – drowsiness, it is very rare – paresthesias, disturbances of memory, a spasm, uneasiness, a tremor, aseptic meningitis, frustration sense of taste, a stroke, disturbance of feeling at a touch.
From an organ of sight: very seldom – a visual disturbance, sight misting, a diplopia.
From an acoustic organ and a labyrinth: often – вертиго, it is very rare – a ring in ears, a hearing disorder.
From heart: very seldom – a heart consciousness, a stethalgia, heart failure, a myocardial infarction.

From vascular system: very seldom – arterial hypertension, a vasculitis.
From a respiratory organs: seldom – asthma (including диспноэ, a bronchospasm, it is very rare – a pneumonitis.

From the alimentary system: often – nausea, vomiting, diarrhea, dyspepsia, abdominal pain, a meteorism, anorexia, it is rare – gastritis, gastrointestinal bleedings, vomiting with blood impurity, hemorrhagic diarrhea, a melena, stomach ulcer or intestines (with bleeding or without it, perforation), is very rare – colitis (including hemorrhagic colitis and an exacerbation of ulcer colitis or a disease Krone), a lock, stomatitis, a glossitis, a dysphagia, diafragmopodobny strictures of a small intestine, pancreatitis.

Gepatobiliarny frustration: often – increase in level of transaminases, is rare – hepatitis, jaundice, an abnormal liver function, is very rare – instant hepatitis, гепатонекроз, a liver failure.

From skin and hypodermic fabrics: often – rash; seldom – a small tortoiseshell;
very seldom – violent rash, eczema, an erythema, different types erity, Stephens-Johnson's syndrome, a toxic epidermal necrolysis (Lyell's disease), exfoliative dermatitis, loss of hair, reaction of photosensitivity, purple, an allergic purpura, an itch.
From kidneys and urinary tract: very seldom – an acute renal failure, a hamaturia, a proteinuria, a nephrotic syndrome, intersticial nephrite, a renal papillary necrosis.

The general disturbances and disturbances in a drug injection site: often – reaction on site injections, pain, hardening, it is rare – hypostasis, a necrosis in the place of an injection.

Interaction with other medicines:

The interactions observed at use of drugs of diclofenac in the form of solution for injections and/or other dosage forms are included below.

Lithium. In the conditions of simultaneous use diclofenac can increase concentration of lithium in a blood plasma. Monitoring of level of lithium in blood serum is recommended.
Digoxin. In the conditions of simultaneous use diclofenac can increase concentration of digoxin in a blood plasma. Monitoring of levels of digoxin in blood serum is recommended.
Diuretics and anti-hypertensive means. As well as can lead other NPVS, the accompanying use of diclofenac with diuretics or anti-hypertensive means (for example, β-blockers, inhibitors of an angiotensin-converting enzyme (APF)) to decrease in their anti-hypertensive action. Thus, the similar combination is applied with care, and patients, especially elderly people, have to be under careful observation of rather arterial pressure. Patients have to receive appropriate hydration, also monitoring of renal function after the beginning of the accompanying therapy and regularly after it, especially for diuretics and APF inhibitors owing to increase in risk of nephrotoxicity is recommended. The accompanying treatment with drugs of potassium can be connected with increase in levels of potassium in blood serum that demands stay of patients under constant control.

Other NPVS and corticosteroids. The accompanying administration of diclofenac and other system NPVS or corticosteroids can increase the frequency of side effects from a GIT.
Anticoagulants and antitrombotichesky means. It is recommended to take precautionary measures as the accompanying introduction can increase risk of bleeding. Though clinical trials do not demonstrate influence of diclofenac on activity of anticoagulants, there are separate data on increase in risk of bleeding at the patients receiving diclofenac and anticoagulants at the same time. Therefore careful monitoring of such patients is recommended.

Selective serotonin reuptake inhibitors (SSRIs). Simultaneous introduction of system NPVS and SSRIs can increase risk of bleeding in a digestive tract.
Anti-diabetic drugs. Clinical trials showed that diclofenac can be applied together with peroral anti-diabetic means without influence on their clinical activity. However separate cases, as with hypoglycemic, and hyper glycemic influence, the demanding changes of a dosage of anti-diabetic means at treatment by diclofenac are known. Such states demand monitoring of levels of glucose in blood that is the warning action at the accompanying therapy.

Holestipol and холестирамин. Simultaneous use of diclofenac and a holestipol or holestiramin reduces diclofenac absorption approximately by 30% and 60% respectively. Drugs should be accepted at an interval of several hours.

The drugs stimulating the enzymes metabolizing medicines. The drugs stimulating enzymes, for example, rifampicin, carbamazepine, Phenytoinum, a St. John's Wort (Hypericum perforatum) are theoretically capable to reduce concentration of diclofenac in plasma.

Methotrexate. At introduction of NPVS less than in 24 hours prior to or after treatment the methotrexate recommends to be careful as concentration of a methotrexate can grow in blood and increase toxicity of this substance.

Cyclosporine and такролимус. Diclofenac, as well as other NPVS, can increase nephrotoxicity of cyclosporine through influence on prostaglandins of kidneys. Such risk arises at treatment takrolimusy. In this regard it should be applied in lower doses, than to patients who do not receive cyclosporine.

Antibacterial hinolona. There are separate data on spasms which can be result of the accompanying use of hinolon and NPVS.

Contraindications:

·        The known hypersensitivity to active ingredient, metabisulphite or to any other components of drug.

·        Allergic reaction to other non-steroidal anti-inflammatory drugs (NPVS), for example, acetylsalicylic acid, an ibuprofen which can be expressed by asthma attacks, rhinitis, rash on skin, a face edema.

· Active stomach ulcer or intestines, bleeding or perforation.

· Severe form of a liver or renal failure.

· The expressed heart failure.

· III trimester of pregnancy.

· Feeding period breast.

· In this dosage form drug is contraindicated to children.

 

Intravenous infusions are contraindicated at:

· simultaneous treatment by other NPVS or anticoagulants (except for low doses of heparin);

· hemorrhagic diathesis in the anamnesis or the confirmed/suspected cerebrovascular bleeding;

· surgical interventions with high risk of bleeding;

· to bronchial asthma in the anamnesis;

· a moderate or heavy renal failure (creatinine level in blood serum> 160 mmol/l);

· hypovolemia or dehydrations of various genesis.

Overdose:

Symptoms. The typical clinical picture of effects of overdose of diclofenac is absent. The overdose can cause such symptoms as vomiting, gastrointestinal bleedings, diarrhea, dizziness, a ring in ears or spasms. In case of a serious poisoning the acute renal failure and damage of a liver is possible.

Treatment. Treatment of acute poisoning of NPVS consists first of all of the supporting actions and a symptomatic treatment. The supporting actions and a symptomatic treatment are necessary for elimination of such complications as hypotension, a renal failure, spasms, gastrointestinal disturbances and respiratory depression.
Special measures, such as artificial diuresis, dialysis or hemoperfusion, cannot guarantee NPVS conclusion owing to their high linkng with proteins of a blood plasma and intensive metabolism.

Storage conditions:

Period of validity 3 years. The prepared solutions for infusion are subject to immediate use. To store in the place, unavailable to children, in original packaging at a temperature not above 25 °C. Not to freeze.

Issue conditions:

According to the recipe

Packaging:

On 3 ml in an ampoule; on 10 ampoules in a box; on 5 ampoules in a blister strip packaging, on 1 or 2 blister strip packagings in a pack.